tbuckley/cabot-search huggingface dataset:
Combination Therapy for <i>EGFR</i> -Mutated Lung Cancer
Authors: Yi-Long Wu, Qing Zhou
Journal: New England Journal of Medicine (2023)

Targeted therapy has improved prognoses for patients with advanced non–small-cell lung cancer (NSCLC) that has epidermal growth factor receptor (EGFR) mutations. The seminal trial that established precision medicine for EGFR-mutated NSCLC was the Iressa Pan-Asia Study (IPASS),1 and a second trial, AURA3, showed that resistance mutations could be detected and then targeted with osimertinib.2 FLAURA was an important third trial that moved osimertinib to the first line of treatment by showing delayed resistance and improved clinical outcomes; progression-free survival was 18.9 months, and overall survival was 38.6 months.3,4 Osimertinib became the standard therapy for advanced NSCLC with EGFR-sensitive mutations. The story . . .
Pharmacological Interpretation of the Efficacy of Ensifentrine in Chronic Obstructive Pulmonary Disease: Insights from ENHANCE Trials
Authors: Luigino Calzetta, Mario Cazzola, Paola Rogliani
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

"Pharmacological Interpretation of the Efficacy of Ensifentrine in COPD: Insights from ENHANCE Trials." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp.
Inhaled Dual PDE3/4 Inhibitor Ensifentrine for Chronic Obstructive Pulmonary Disease: A Potential Therapeutic Perspective
Authors: Qiming Gan, Yanjuan Wu, Xiaofen Su, Jingcun Wang, Haojie Zhang, Nuofu Zhang, Kang Wu
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

"Inhaled Dual PDE3/4 Inhibitor Ensifentrine for COPD: A Potential Therapeutic Perspective." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp.
Novel community data in ecology-properties and prospects
Authors: Florian Hartig, Nerea Abrego, Alex Bush, Jonathan M. Chase, Gurutzeta Guillera-Arroita, Mathew A. Leibold, Otso Ovaskainen, Loïc Pellissier, Maximilian Pichler, Giovanni Poggiato, Laura Pollock, Sara Si-Moussi, Wilfried Thuiller, Duarte S. Viana, David I. Warton, Damaris Zurell, Douglas W. Yu
Journal: Trends in Ecology & Evolution (2023)
Why health-care learners and professionals should want to learn about medicine, Nazism, and the Holocaust
Authors: Shani Levany, Muhammad Athallah Arsyaf, Cristina Bejarano Roma, Shubham Gupta Lalbabuprasad, Chinyere Jennifer Igwe, Yimeng Jin, Clemens Jobst, Georgia Livieri, Dali Majeed, Emma Nalianya, Mercedes Prodromou, Catherine Read, Max Stone, Rounak Verma
Journal: The Lancet (2023)
Ecological diversity profiles of non-vaccine-targeted HPVs after gender-based community vaccination efforts
Authors: Ville N. Pimenoff, Penelope Gray, Karolina Louvanto, Tiina Eriksson, Camilla Lagheden, Anna Söderlund-Strand, Joakim Dillner, Matti Lehtinen
Journal: Cell Host & Microbe (2023)

The long-term effect of population-level human papillomavirus (HPV) vaccination on the viral ecology of the untargeted HPVs is poorly understood. We performed an 8-year follow-up of 33 communities randomized to gender-neutral HPV16/18 vaccination, girls-only HPV16/18 vaccination, and control communities without HPV vaccination. The 1992/93 and 1994 birth cohorts were invited in school years 2007/8 and 2008/9. Follow-up cervico-vaginal sampling at 18 and 22 years of age, 4 and 8 years post-vaccination, respectively, were attended by 11,396 and 5,602 participants. HPV types 6/11/16/18/31/33/35/39/45/51/52/56/58/59/66/68 were genotyped and used for the community-level ecological diversity estimations. Gender-neutral vaccination communities with a stronger herd immunity than girls-only vaccination communities show a significantly increased HPV α-diversity (p = 1.1 × 10-8) from 4 to 8 years post-vaccination, despite the clearance of the vaccine-targeted HPVs in these communities. This likely sign of niche occupation by the non-vaccine-targeted HPVs will potentially affect the future cervical cancer screening programs but should not interfere with the WHO mission to eliminate cervical cancer.
The plant immune receptor SNC1 monitors helper NLRs targeted by a bacterial effector
Authors: Ming-Yu Wang, Jun-Bin Chen, Rui Wu, Hai-Long Guo, Yan Chen, Zhen-Ju Li, Lu-Yang Wei, Chuang Liu, Sheng-Feng He, Mei-Da Du, Ya-long Guo, You-Liang Peng, Jonathan D.G. Jones, Detlef Weigel, Jian-Hua Huang, Wang-Sheng Zhu
Journal: Cell Host & Microbe (2023)
Racial Disparities in Receipt of Guideline-Concordant Care for Early-Onset Colorectal Cancer in the United States
Authors: Leticia M. Nogueira, Folasade P. May, K. Robin Yabroff, Rebecca L. Siegel
Journal: Journal of Clinical Oncology (2023)

Young individuals racialized as Black are more likely to die after a colorectal cancer (CRC) diagnosis than individuals racialized as White in the United States. This study examined racial disparities in receipt of timely and guideline-concordant care among individuals racialized as Black and White with early-onset CRC.
Multi-kingdom gut microbiota analyses define bacterial-fungal interplay and microbial markers of pan-cancer immunotherapy across cohorts
Authors: Xiaowen Huang, Muni Hu, Tiantian Sun, Jiantao Li, Yilu Zhou, Yuqing Yan, Baoqin Xuan, Jilin Wang, Hua Xiong, Linhua Ji, Xiaoqiang Zhu, Tianying Tong, Lijun Ning, Yanru Ma, Ying Zhao, Jinmei Ding, Zhigang Guo, Youwei Zhang, Jing-Yuan Fang, Jie Hong, Haoyan Chen
Journal: Cell Host & Microbe (2023)
AASLD Practice Guidance on Acute-on-chronic liver failure and the management of critically ill patients with cirrhosis
Authors: Constantine J. Karvellas, Jasmohan S. Bajaj, Patrick S. Kamath, Lena Napolitano, Jacqueline G. O’Leary, Elsa Solà, Ram Subramanian, Florence Wong, Sumeet K. Asrani
Journal: Hepatology (2023)

Karvellas, Constantine J.; Bajaj, Jasmohan S.; Kamath, Patrick S.; Napolitano, Lena; O'Leary, Jacqueline G.; Solà, Elsa; Subramanian, Ram; Wong, Florence; Asrani, Sumeet K. Author Information
A systematic review of chronobiology for neonatal care units: What we know and what we should consider
Authors: Philip Lewis, Ursula Wild, J. Jane Pillow, Russell G. Foster, Thomas C. Erren
Journal: Sleep Medicine Reviews (2023)

A Cochrane 2016 review indicated cycled light might benefit neonatal health in hospital. We systematically reviewed chronobiological factors for neonatal health in hospital units, identifying 56 relevant studies on light-dark cycles, feeding, noise, massage therapy, rooming-in, incubators vs. cribs, neonatal units vs. homes, and time-of-day of birth. Empirical evidence for benefits from chronobiology is weaker than expected, including light. Mechanisms of clinical benefits are unclear (e.g., changes to sleep/activity vs. other circadian-regulated processes). Regarding light, studies concerning sleep and circadian-related outcomes predominate; yet, neonatologists may be more interested in weight gain and time spent in hospital. Generalisability of findings is limited as most studies targeted neonates in stable condition and without congenital anomalies. Further research is needed, in particular concerning potential circadian entraining signals such as timing of meals or medications. Longer-term outcomes (regarding e.g., neurodevelopment and infection), and who may be at risk from time-of-day of birth effects and why remain to be explored. Overall, there is promise and ample scope for research into how chronobiological factors affect health in hospitalised neonates.
Access to Care for Adolescents and Young Adults With Cancer in the United States: State of the Literature
Authors: Anne C. Kirchhoff, Austin R. Waters, Amy Chevrier, Julie A. Wolfson
Journal: Journal of Clinical Oncology (2023)

Access to care remains a persistent challenge for adolescents and young adults (AYAs) with cancer. We review key findings in the science to date. (1) Location of care matters. There is survival benefit for AYAs treated either at a pediatric center or site with special status (eg, Children's Oncology Group, National Cancer Institute [NCI]-designated Comprehensive Cancer Center). (2) Socioeconomic status and insurance require further investigation. Medicaid expansion has had a moderate effect on AYA outcomes. The dependent care expansion benefit has come largely from improvements in coverage for younger populations whose parents have insurance, while some subgroups likely still face insurance gaps. (3) Clinical trial enrollment remains poor, but access may be improving. Numerous barriers and facilitators of clinical trial enrollment include those that are system level and patient level. NCI has established several initiatives over the past decade to improve enrollment, and newer collaboratives have recently brought together multidisciplinary US teams to increase clinical trial enrollment. (4) Effective AYA programs require provider and system flexibility and program reflection. With flexibility comes a need for metrics to assess program effectiveness in the context of the program model. Centers treating AYAs with cancer could submit a subset of metrics (appropriate to their program and/or services) to maintain their status; persistence would require an entity with staying power committed to overseeing the metrics and the system. Substantial clinical and biological advances are anticipated over the next 20 years that will benefit all patients with cancer. In parallel, it is crucial to prioritize research regarding access to health care and cancer care delivery; only with equitable access to care for AYAs can they, too, benefit from these advances.
Bioorthogonal microglia-inspired mesenchymal stem cell bioengineering system creates livable niches for enhancing ischemic stroke recovery via the hormesis
Authors: Jianpei Xu, Yinzhe Sun, Yang You, Yuwen Zhang, Dan Huang, Songlei Zhou, Yipu Liu, Shiqiang Tong, Fenfen Ma, Qingxiang Song, Chengxiang Dai, Suke Li, Jigang Lei, Zhihua Wang, Xiaoling Gao, Jun Chen
Journal: Acta Pharmaceutica Sinica B (2023)

Mesenchymal stem cells (MSCs) experience substantial viability issues in the stroke infarct region, limiting their therapeutic efficacy and clinical translation. High levels of deadly reactive oxygen radicals (ROS) and proinflammatory cytokines (PC) in the infarct milieu kill transplanted MSCs, whereas low levels of beneficial ROS and PC stimulate and improve engrafted MSCs' viability. Based on the intrinsic hormesis effects in cellular biology, we built a microglia-inspired MSC bioengineering system to transform detrimental high-level ROS and PC into vitality enhancers for strengthening MSC therapy. This system is achieved by bioorthogonally arming metabolic glycoengineered MSCs with microglial membrane-coated nanoparticles and an antioxidative extracellular protective layer. In this system, extracellular ROS-scavenging and PC-absorbing layers effectively buffer the deleterious effects and establish a micro-livable niche at the level of a single MSC for transplantation. Meanwhile, the infarct's inanimate milieu is transformed at the tissue level into a new living niche to facilitate healing. The engineered MSCs achieved viability five times higher than natural MSCs at seven days after transplantation and exhibited a superior therapeutic effect for stroke recovery up to 28 days. This vitality-augmented system demonstrates the potential to accelerate the clinical translation of MSC treatment and boost stroke recovery.
Structure-based development of potent and selective type-II kinase inhibitors of RIPK1
Authors: Ying Qin, Dekang Li, Chunting Qi, Huaijiang Xiang, Huyan Meng, Jingli Liu, Shaoqing Zhou, Xinyu Gong, Ying Li, Guifang Xu, Rui Zu, Hang Xie, Yechun Xu, Gang Xu, Zheng Zhang, Shi Chen, Lifeng Pan, Ying Li, Li Tan
Journal: Acta Pharmaceutica Sinica B (2023)

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions as a key regulator in inflammation and cell death and is involved in mediating a variety of inflammatory or degenerative diseases. A number of allosteric RIPK1 inhibitors (RIPK1i) have been developed, and some of them have already advanced into clinical evaluation. Recently, selective RIPK1i that interact with both the allosteric pocket and the ATP-binding site of RIPK1 have started to emerge. Here, we report the rational development of a new series of type-II RIPK1i based on the rediscovery of a reported but mechanistically atypical RIPK3i. We also describe the structure-guided lead optimization of a potent, selective, and orally bioavailable RIPK1i, 62, which exhibits extraordinary efficacies in mouse models of acute or chronic inflammatory diseases. Collectively, 62 provides a useful tool for evaluating RIPK1 in animal disease models and a promising lead for further drug development.
Reply: Comparing quantitative MRI technologies in steatotic liver disease
Authors: Jiahui Li, Alina M. Allen, Meng Yin
Journal: Hepatology (2023)

1Department of Radiology, Mayo Clinic, Rochester, MN 2Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN Correspondence Meng Yin, Department of Radiology, Mayo Clinic, Rochester, MN. Email: [email protected]
Endoscopic Transcecal Appendectomy With a Novel Detachable Over-the-Scope Clip
Authors: Fu Guan, Mingqing Zhang, Shengbing Wang
Journal: Clinical Gastroenterology and Hepatology (2023)

A 50-year-old woman presented with right lower-abdominal pain for more than 1 month. Colonoscopy revealed a 1.8-cm submucosal bulge near the appendiceal orifice (Figure A). Computed tomography, magnetic resonance imaging, and endoscopic ultrasound were suspicious for appendiceal mucocele. The patient declined laparoscopic or conventional surgical appendectomy, but agreed to endoscopic transcecal appendectomy (ETA) after multidisciplinary discussion. The procedure steps were as follows (Supplementary Video): the appendiceal lesion margin was marked using a woodpecker I-knife (multifunctional knife, Anrei); a full-thickness circumferential incision was made along the marks and the appendiceal orifice with the woodpecker knife (I- and O-knife); the root of the partially dissected appendix was retracted using a snare to adequately expose the incision line and continue dissection; the woodpecker knife (O-knife) was used to dissect the mesoappendix along the appendix, and mesentery vessels were coagulated with hot biopsy forceps; the appendix and lesion were completely removed with a snare via the anus; and the defect was closed with a novel detachable over-the-scope clip (OTSC) (Senscure) (Figure B) and hemostatic clips. Pathologic assessment confirmed an appendiceal retention mucocele. The patient was discharged 7 days after ETA with no abdominal pain and no complications. The resected area was healing at follow-up colonoscopy after 2 months (Figure C). The OTSC and hemostatic clips were removed during this procedure (Figure D). No delayed complications were noted. ETA is a viable treatment option for patients unable or unwilling to undergo surgery. We report a case of defect closure after ETA using a novel detachable OTSC. eyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiI2ZWM1ZTc3NDQyYWVlZGNiMzg1ZjU0NTQ0MmVhM2YwNyIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNzE1NTg4ODY5fQ.kGKbqJ_THFxiLYF2ZdFmzFxed-F_sVxGkw8atVP44NqIRxYQ5WvK10dKqvcnyuQaRxdsaPdyyQ53aLvjbYMGWuhynkBeS26usX0lg33nOGqwnU4V1QKz4A9rOXxPzzGblc15mrZFXeeHkvrbvsMCOnmbqBr9ztOGqS0eSAea8iHnA_a2PRGCQl8NMkSEnBqzZSQw3uBLb3mxGLTByqLFKK73zxCUpR8oK-Rjsu34v1QycG6-YRx9MeyRR2QkinLQoe0Ms4kf0IXF94imLnRY9dovO1GPiQ8eVF4HpDvI7Fp-3FOrIM2fz_UafBsKe2kWb9hVu41VSOqBaTaOaS4pyQ Download .mp4 (39.91 MB) Help with .mp4 files Video
Psoriasiform mycosis fungoides: a clinical and prognostic retrospective cohort study
Authors: Joon Min Jung, Hye Soo Cho, Gyeong Hoon Kim, Chong Hyun Won, Sung Eun Chang, Chan Sik Park, Mi Woo Lee, Woo Jin Lee
Journal: British Journal of Dermatology (2023)

The psoriasiform manifestation of mycosis fungoides (MF) was identified in 17.5% of patients in this study. Psoriasiform MF had a shorter prediagnosis period than the other subtypes. Psoriasiform MF was associated with advanced stage, lymph node involvement and large cell transformation, and was thus also associated with poor survival.
Inhibition of ATR opposes glioblastoma invasion through disruption of cytoskeletal networks and integrin internalization via macropinocytosis
Authors: Sarah J Derby, Louise Dutton, Karen E Strathdee, Katrina Stevenson, Anna Koessinger, Mark Jackson, Yuling Tian, Wenxi Yu, Kathy Mclay, Josette Misquitta, Sama Alsharif, Cassie J Clarke, Lesley Gilmour, Peter Thomason, Ewan McGhee, Connor L McGarrity-Cottrell, Aurelie Vanderlinden, Spencer J Collis, Ola Rominyi, Leandro Lemgruber, Gergely Solecki, Michael Olson, Frank Winkler, Leo M Carlin, Dieter Henrik Heiland, Gareth J Inman, Anthony J Chalmers, Jim C Norman, Ross Carruthers, Joanna L Birch
Journal: Neuro-Oncology (2023)

Abstract Background Glioblastomas have highly infiltrative growth patterns that contribute to recurrence and poor survival. Despite infiltration being a critical therapeutic target, no clinically useful therapies exist that counter glioblastoma invasion. Here, we report that inhibition of ataxia telangiectasia and Rad 3 related kinase (ATR) reduces invasion of glioblastoma cells through dysregulation of cytoskeletal networks and subsequent integrin trafficking. Methods Glioblastoma motility and invasion were assessed in vitro and in vivo in response to ATR inhibition (ATRi) and ATR overexpression using time-lapse microscopy, two orthotopic glioblastoma models, and intravital imaging. Disruption to cytoskeleton networks and endocytic processing were investigated via high-throughput, super-resolution and intravital imaging. Results High ATR expression was associated with significantly poorer survival in clinical datasets while histological, protein expression, and spatial transcriptomics using glioblastoma tumor specimens revealed higher ATR expression at infiltrative margins. Pharmacological inhibition with two different compounds and RNAi targeting of ATR opposed the invasion of glioblastoma, whereas overexpression of ATR drove migration. Subsequent investigation revealed that cytoskeletal dysregulation reduced macropinocytotic internalization of integrins at growth-cone-like structures, resulting in a tumor microtube retraction defect. The biological relevance and translational potential of these findings were confirmed using two orthotopic in vivo models of glioblastoma and intravital imaging. Conclusions We demonstrate a novel role for ATR in determining invasion in glioblastoma cells and propose that pharmacological targeting of ATR could have far-reaching clinical benefits beyond radiosensitization.
Central and peripheral innate and adaptive immunity in Parkinson’s disease
Authors: Ashley S. Harms, Ya-Ting Yang, Malú Gámez Tansey
Journal: Science Translational Medicine (2023)

Parkinson’s disease (PD) is a multisystem disorder with characteristics of a chronic inflammatory disease. To develop effective immunomodulatory interventions to combat PD, we need to think innovatively about the implications of orchestrated central and peripheral innate and adaptive immune responses that occur as the disease begins and progresses.
High expression of interleukin-17A in cutaneous sarcoidosis
Authors: Stephanie V Shimon, Karishma Desai, Mariya Miteva, Mehrdad Nadji, Paolo Romanelli
Journal: British Journal of Dermatology (2023)

Increasing evidence of Th17 pathways is implicated in sarcoidosis granulomatous inflammation and maintenance. Our study evaluated the presence of IL-17A, a downstream proinflammatory cytokine, in cutaneous sarcoidosis biopsies. We found that all 26 biopsy samples had increased expression of IL-17A, predominantly located in macrophages within granulomas, in the cytoplasm of multinucleated histiocytes surrounding the granulomas and within lymphocytic infiltrates surrounding the inflammation.
Implications of Mean Pulmonary Arterial Wedge Pressure Trajectories in Pulmonary Arterial Hypertension
Authors: Eileen M. Harder, Miguel J. Divo, George R. Washko, Jane A. Leopold, Farbod N. Rahaghi, Aaron B. Waxman
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

Rationale: The mean pulmonary arterial wedge pressure (mPAWP) is the critical hemodynamic factor differentiating group 1 pulmonary arterial hypertension (PAH) from group 2 pulmonary hypertension associated with left heart disease. Despite the discrepancy between the mPAWP upper physiologic normal and current PAH definitions, the implications of the initial mPAWP for PAH clinical trajectory are poorly understood. Objectives: To model longitudinal mPAWP trajectories in PAH over 10 years and examine the clinical and hemodynamic factors associated with trajectory membership. Methods: Adult patients with PAH with two or more right heart catheterizations were identified from a multiinstitution healthcare system in eastern Massachusetts. mPAWP trajectories were constructed via group-based trajectory modeling. Feature selection was performed in least absolute shrinkage and selection operator regression. Logistic regression was used to assess associations between trajectory membership, baseline characteristics, and transplant-free survival. Measurements and Main Results: Among 301 patients with PAH, there were two distinct mPAWP trajectories, termed "mPAWP-high" (n = 71; 23.6%) and "mPAWP-low" (n = 230; 76.4%), based on the ultimate mPAWP value. Initial mPAWP clustered around median 12 mm Hg (interquartile range [IQR], 8–14 mm Hg) in the mPAWP-high and 9 mm Hg (IQR, 6–11 mm Hg) in the mPAWP-low trajectories (P < 0.001). After feature selection, initial mPAWP ⩾12 mm Hg predicted an mPAWP-high trajectory (odds ratio, 3.2; 95% confidence interval, 1.4–6.1; P = 0.0006). An mPAWP-high trajectory was associated with shorter transplant-free survival (vs. mPAWP-low, median, 7.8 vs. 11.3 yr; log-rank P = 0.017; age-adjusted P = 0.217). Conclusions: Over 10 years, the mPAWP followed two distinct trajectories, with 25% evolving into group 2 pulmonary hypertension physiology. Using routine baseline data, longitudinal mPAWP trajectory could be predicted accurately, with initial mPAWP ⩾12 mm Hg as one of the strongest predictors.
An analysis of inter- and intra-rater Facial Vitiligo Area Scoring Index assessments in adults with active nonsegmental vitiligo
Authors: Anindita Banerjee, Khaled Ezzedine, Ronald Shore, Elena Peeva, Yuji Yamaguchi, Lori Cox, Abigail Sloan, Margaret Gamalo, Christian Russel Reyes
Journal: British Journal of Dermatology (2023)

With several vitiligo therapies currently under development, a reliable clinician-reported outcome is needed to assess disease severity and treatment response. The objective of the current study was to evaluate the inter- and intra-rater reliabilities of the F-VASI in assessing the extent and severity of vitiligo in a central reader paradigm as part of a clinical trial of the oral dual Janus kinase 3/Tec family kinase inhibitor ritlecitinib in patients with vitiligo. We found strong and consistent inter-rater agreement between two central readers across all F-VASI measurements and observed similar reliability for intra-rater assessments across two separate readings of the same patient images.